Pharmaceutical composition for topical applications

ABSTRACT

Non-greasy topical solutions, emulsion gels or lotions comprising as the active agent a compound of formula I ##STR1## and a lower alkanol, and if desired together with a solubilizing agent or an oil phase such as isopropyl myristate are useful delivery systems.

This is a continuation of application Ser. No. 07/884,681, filed May 18,1992, now abandoned.

The present invention relates to topical pharmaceutical compositions,such as solutions, gels, fluid gels, emulsion gels and lotionscontaining an allylamine compound as the pharmacologically active agent.

The present invention provides a topical pharmaceutical composition,comprising as the active agent a compound of formula I ##STR2## and alower alkanol.

Such compositions may be for example non-greasy solutions, emulsion gelsor lotions, all being liquid or viscous.

In another aspect the present invention provides a process for thepreparation of a topical pharmaceutical composition, comprising workingup a compound of formula I above together with a lower alkanol andadding further excipients as appropriate.

Examples of topical solutions contemplated under the present inventionare solutions per se or are spray liquids, gels or fluid gels.

Water is preferably present in the compositions according to theinvention, e.g. in concentrations by weight from e.g. 50 to 85%.

The compound of formula I may be e.g. in free base form or in acidaddition salt form. An acid addition salt form may be prepared from thefree base form in conventional manner and vice-versa. Examples ofsuitable acid addition salt forms are the hydrochloride, the lactate andthe ascorbate.

The compound of formula I is known from e.g. BE-PS-853976 andEP-A-24587. It belongs to the class of allylamine anti-mycotics. It hasthe generic name terbinafine and is commercially available under thetradename LAMISIL. Whereas terbinafine is highly active upon bothtopical and oral application, we have found that the only topicalformulation for wide-spread use, a cream in which the drug is keptdissolved in the organic phase, only partly fulfills the patients'needs, as it is only a convenient formulation for selected diseasestates and skin types. A topical formulation in the form of acomposition according to the invention is highly desirable as it offersseveral advantages e.g. in application properties, in comparison toclassical formulations such as creams, e.g.

faster and more complete release of the drug from the vehicle to theskin and therefore higher efficacy;

absence of greasiness and no residue upon application and thereforeincreased convenience for application on haired skin;

improved spreadability on the skin and thus better convenience forapplication on larger skin parts; and

cooling effect on the skin and therefore better convenience forapplication on seborrhoic skin.

The preparation of topical compositions offering the improved propertiesmentioned above, however, is difficult with the compound of formula Idue to the low solubility of the drug in aqueous systems, the tendencyof the compound when used in acid addition salt form or as an oil basedemulsion gel or lotion, to separate from the medium as the free base, asdroplets or even in crystalline form, as we have found the free base isless soluble in water than the corresponding acid addition salts and dueto the tendency of the drug to interact with anionic excipients. Usingthe acid addition salt form is desirable and also the preferredembodiment of this invention, because the solubility of the drug inaqueous systems may be improved. However, separating of the free basefrom the equilibrium present in compositions according to presentinvention presents a serious problem with respect to the reproducabilityof the pharmacological effect, and to the shelf life stability of suchproduct.

The above difficulties are exacerbated when attempting to prepareone-phase formulations such as fluid gels and gels containing thecompound of formula I in free base or salt form in the same phase incombination with the classical Carbomer thickeners (polyacrylic acidderivatives) which is a typical excipient for gels. We have observedthat there is an interaction of the components, resulting in aninsoluble complex or in crystallization of the base. There is thus aneed for improved topical forms e.g. fluid gels and gels.

As outlined above, this problem can according to one aspect of thisinvention be circumvented by formulating an emulsion system where thefree base is dissolved in the oily phase. However these systems may notbe suitable for certain kinds of skin type and disease state as in manysituations a formulation substantially free of fatty materials such asfatty acids, fatty acid esters and fatty alcohols such as e.g.polyethylene stearates or palmitates, cetyl stearates or palmitates,stearyl or cetyl alcohols, is preferred. A clear solution is also highlydesirable as an improved topical formulation. There is thus also a needfor such improved forms which are based on water and do not contain oilsor fats and wherein the free base present at equilibrium remains insolution.

According to another aspect of the invention, it has now been found thatthe separation of the free base in water-based solutions may be avoidede.g. for the topical solutions by the addition of suitable solubilizingagents in the formulations, which are non-ionic, e.g. there is noanionic surfactant present. These agents should preferably besurfactants which are water-soluble or water-miscible and compatiblewith the drug substance and any further excipients present in theformulation, and they should be well tolerated on the skin.

Further, a desirable feature of the contemplated solubilizers is apenetration-enhancing effect for the drug substance without causing anyirritation on the skin.

Examples of suitable solubilizing agents for the topical solutions are:

a) Reaction products of a natural or hydrogenated castor oil andethylene oxide. Such products may be obtained in known manner, e.g. byreaction of a natural or hydrogenated castor oil with ethylene oxide,e.g. in a molar ratio of from about 1:35 to about 1:60, with optionalremoval of the polyethyleneglycol component from the product, e.g. inaccordance with the methods disclosed in DOS 1'182'388 and 1'518'819.Especially suitable are the various tensides available under thetradename Cremophor. Particularly suitable are the products:

Cremophor RH 40 having a saponification number of about 50-60, an acidnumber<1, an iodine number<1, a water content (Fischer)<2%, an n_(D) ⁶⁰of about 1.453-1.457 and an HLB of about 14-16;

Cremophor RH 60 having a saponification number of about 40-50, an acidnumber<1, an iodine number<1, a water content (Fischer) 4.5-5.5%, ann_(D) ²⁵ of about 1.453-1.457 and an HLB of about 15-17; and

Cremophor EL having a molecular weight (by steam osmometry) of about1630, a saponification number of about 65-70, an acid number of about 2,an iodine number of about 28-32 and an n_(D) ²⁵ of about 1.471.

Also suitable for use in this category are the various tensidesavailable under the tradename Nikkol, e.g. Nikkol HCO-60. Nikkol HCO-60is a reaction product of hydrogenated castor oil and ethylene oxideexhibiting the following characteristics: acid number of 0.3;saponification number of 47.4; hydroxy value of 42.5; pH (5%) of 4.6;color APHA=40; M.P.=36.0° C.; freezing point=32.4° C.; H₂ O content (%,KF)=0.03;

b) polyoxyethylene-sorbitan-fatty acid esters or polysorbates, e.g. ofthe type known and commercially available under the tradenames Tween(Fiedler 2, p.1300-1304) and Armoran (Fiedler 1, p. 172) including theproducts

Tween 20 polyoxyethylene(20)sorbitanmonolaurate!;

Tween 40 polyoxyethylene(20)sorbitanmonopalmitate!;

Tween 60 polyoxyethylene(20)sorbitanmonostearate!;

Tween 65 polyoxyethylene(20)sorbitantristearate!;

Tween 80 polyoxyethylene(20)sorbitanmonooleate!;

Tween 85 polyoxyethylene(20)sorbitantrioleate!;

Tween 21 polyoxyethylene(4)sorbitanmonolaurate!;

Tween 61 polyoxyethylene(4)sorbitanmonostearate!; and

Tween 81 polyoxyethylene(5)sorbitanmonooleate;

c) polyoxyethylene fatty acid esters, for example polyoxyethylenestearic acid esters of the type known and commercially available underthe Tradename Myrj (Fiedler 2, p. 834-835) as well as polyoxyethylenefatty acid esters known and commercially available under the tradenameCetiol HE (Fiedler 1, p. 283-284);

d) polyoxyethylene-polyoxypropylene co-polymers e.g. of the type knownand commercially available under the tradenames Pluronic and Emkalyx(Fiedler 2, p. 956-958);

e) polyoxyethylene fatty alcohol ethers, for example polyoxyethylenestearyl ether, oleyl ether, or cetyl ether, e.g. of the type known underthe tradename Brij (Fiedler 1, p. 222-224), e.g. Brij 78 and 96, andCetomacrogol 1000 (Fiedler 1, p. 284).

Preferred solubilizing agents are those under a), b), c) and e),particularly Cetomacrogol 1000^(R), Cremophor RH40^(R) and Tween 20^(R).Especially preferred is Cetomacrogol 1000^(R).

The compound of formula I and the solubilizing agent are preferablypresent in the topical-solution composition in the proportion of fromabout 1:0.5 to about 1:15, preferably from about 1:1 to about 1:10 on aw/w basis. The compound of formula I preferably makes up from about 0.1%to about 5%, preferably from about 0.5% to about 2% of the totalcomposition on a weight basis.

In their simplest form the topical solutions of this invention onlycomprise the drug substance, the solubilizer and the lower alkanolicsolvent. The alkanolic solvent is preferably mixed with water when usedin a composition according to the invention. Lower alkanolic solventsaccording to the invention are physiologically acceptable C₁ -C₄alcohols e.g. isopropanol or preferably ethanol. The concentration byweight of the alkanol in the composition may range e.g. from about 5% toabout 90%, e.g. from about 5% to about 35%. A typical concentration isfrom about 25% to about 45% for a fluid composition, e.g. from 25 to35%, and for a viscous composition, e.g. a gel from about 5 to about15%, e.g.10%.

The solutions may be filled into conventional glass bottles with adropping device or into more elaborate devices, e.g. plastic bottles orplastic bottles with spraying device.

Due to easier application a thickened solution, e.g. a fluid-gel or atransparent gel may be desirable. This can be achieved by addingconventional thickeners to the solutions described above. Suitablecomponents include for example:

polymethylacrylate resins, e.g. of the type known and commerciallyavailable under the tradename Eudispert (Fiedler 1, p. 485-486);

cellulose derivatives including e.g. ethyl-, propyl-, methyl- andhydroxypropylmethyl-celluloses;

polyvinyl resins, e.g. including polyvinylalcohols andpolyvinyl-pyrrolidones, as well as other polymeric materials includinggelatin, alginates, pectins, gum traganth, gum arabicum and gumxanthane;

materials such as silica gel, bentonite, and magnesium-aluminiumsilicate.

These components when present are suitably present in an amount of up to20%, more preferably up to 10%, based on the total weight of thecomposition. Most suitably they are present in an amount of from about0.5% to about 15%, e.g. from about 1.0% to about 3.0% based on the totalweight of the composition.

The topical solution preparations of the invention can be obtained by aprocess comprising dissolving the compound of formula I in free baseform or in acid addition salt form together with the solubilizer in anappropriate vehicle and adding further excipients as appropriate. If athickened solution or a gel is desired the thickener is added inconventional manner to the system. The process of the invention may beeffected in conventional manner.

According to a further aspect of the invention stable emulsion gels andlotions are provided. Where an emulsion gel or a lotion based on acarbomer thickener is required in order to administer the compound offormula I to the skin, the problems associated with the interaction ofthe free base with the anionic polymer are in principle the same as withthe above aqueous solutions. It has now been found that theseinteractions may be avoided and stable emulsion gels and lotions may beobtained when an oily phase, such as isopropyl myristate, is added tothe compound of formula I, preferably in free base form, and thecarbomer. This results in stable emulsion gels and lotions which haveall the beneficial properties of a gel and avoid the interaction of thedrug with the carbomer.

In emulsion gels and lotions according to the invention the compound offormula I and an oil phase are present in the emulsion gels and lotionsin the proportion of from about 1:5 to about 1:40, preferably from about1:7 to about 1:20 on a w/w basis. The oil phase is preferably isopropylmyristate. It is preferably present in a concentration by weight of 10%.The compound of formula I preferably makes up from about 0.1% to about5%, preferably from about 0.5% to about 3% of the total composition on aweight basis. Preferably the amount of lower alkanol, water and oilphase, if present, is from about 83 to about 96% by weight of thecomposition. Conventional further excipients are in particularthickeners such as carbomers (polyacrylic acid derivatives) as known andcommercially available under the tradename Carbopol (Fiedler 1, p.206-207), e.g. Carbopol 934 P or Carbopol 1342. Further excipients are,e.g. emulsifiers such as sorbitan monolaurate (Span 20^(R)) andpolysorbate 20 (Tween 20^(R)); however, it has been observed that withthe compound of formula I the carbomers stabilize the emulsion to theextent that only little or no emulgator at all is necessary to achievestable emulsion gels and lotions, particularly when the carbomer isCarbopol 1342.

The resulting emulsion gels and lotions possess improved cosmeticproperties, such as facilitated spreading on the skin and absence ofgreasing; in view of the reduced amount or absence of conventionalemulsifiers, they also possess improved pharmacological properties, inparticular better tolerability when applied to infected and ofteninflamed skin. A further advantage of the present invention is that theappearance and consistency of the final formulation may be freelyregulated by varying the proportion of thickening agent (carbomer) inthe formulation.

The emulsion gels and lotions of the invention may be obtained by aprocess comprising dissolving a compound of formula I in free base formor in acid addition salt form and further excipients as appropriate,e.g. in an appropriate oil phase such as isopropyl myristate .

The oil phase may be emulsified with an appropriate water phase and thenincorporated into a pre-prepared gel concentrate containing the carbomerand further excipients as appropriate. This mode of manufacturing avoidsthe interaction between the compound of formula I and the carbomerduring the process. Preferably the carbomer is neutralized before beingmixed with the oil phase.

The formulations may contain additional ingredients, e.g.

complexing agents, e.g. ethylendiamine-tetraacetate (disodium salt);

flavours;

colourants.

The compositions according to present invention may also containconventional additives to adjust the pH-value to an acceptable value forskin treatment. This may be achieved by adding a pharmaceuticallyacceptable base or acid and adjusting the pH-value or by adding apharmaceutically acceptable buffer system to the composition.Additionally, the compositions may contain preserving agents and/orantioxidants, e.g. an amount of 0.05 to 1% by weight of the total weightof the composition, e.g. ascorbyl palmitate, sodium pyrosulfite, butylhydroxy anisole (BHA), butyl hydroxy toluene (BHT), tocopherols, e.g.α-tocopherol (vitamin E), benzyl alcohol, propyl- or methylp-hydroxybenzoates.

The compositions of the invention are useful for the same indications asknown for other topical compositions, e.g. fungal infections and in thesame dosages , e.g. as confirmed by standard clinical trials. Typicaleffective dosages are achieved when the active agent concentration inthe treated skin tissue is between 10 and 10'000 ng per squarecentimeter. Preferred skin tissue concentrations are between 500 and2000 ng per square centimeter e.g. 1000 ng per square centimeter e.g. asindicated in standard pharmacological tests. However higher and lowerdosages may be effective and may be determined by standard tests. Forexample the effective concentrations in the treated skin may be achievedwhen applying e.g. the compound of formula I in form of e.g. a 1%composition according to the invention over the infected area, e.g. 5 mgactive agent per day to a skin area of about 100 square centimeters.

The following Examples illustrate the invention. All temperatures are indegrees Centigrade (r.t.=room temperature):

EXAMPLE 1 Topical Solution 1% (Spray 1%)

    ______________________________________                                        Ingredient          Amount (g/100 g)                                          ______________________________________                                        Compound I in hydrochloride form                                                                  1.0                                                       Polyethoxy-20-cetylstearyl                                                                        2.0                                                       ether (e.g. Cetomacrogol 1000)                                                Propylene glycol    5.0                                                       Ethanol 94 % w/w    25.0                                                      Water demineralized 67.0                                                      ______________________________________                                    

EXAMPLE 2 Gel 1%

    ______________________________________                                        Ingredient          Amount (g/100 g)                                          ______________________________________                                        Compound I in hydrochloride form                                                                  1.00                                                      Disodium edetate dihydrate                                                                        0.02                                                      (e.g. Komplexon III)                                                          Polysorbate 20 (e.g. Tween 20)                                                                    2.0                                                       Sodium pyrosulfite  0.02                                                      Propylene glycol    0.70                                                      Hydroxypropyl cellulose                                                                           1.50                                                      (e.g. Klucel HF)                                                              Ethanol 94 % w/w    35.00                                                     Water demineralized 59.76                                                     ______________________________________                                    

EXAMPLE 3 Fluid Gel 1%

    ______________________________________                                        Ingredient            Amount (g/100 g)                                        ______________________________________                                        Compound I in hydrochloride form                                                                    1.00                                                    Disodium edetate dihydrate                                                                          0.02                                                    (e.g. Komplexon III)                                                          Sodium pyrosulfite    0.02                                                    Polyethoxy-40-hydrogenated                                                                          1.00                                                    castor oil (e.g. Cremophor RH40)                                              Hydroxypropyl cellulose (e.g. Klucel GF)                                                            2.00                                                    Ethanol 94 % w/w      35.00                                                   Water demineralized   60.96                                                   ______________________________________                                    

EXAMPLE 4 Emulsion Gel 1%

    ______________________________________                                        Ingredient            Amount (g/100 g)                                        ______________________________________                                        A)    Compound I in free base form                                                                      1.00                                                C)    Butyl hydroxy toluene                                                                             0.02                                                I)    Sodium hydroxide pellets                                                                          0.10                                                D)    Benzyl alcohol      1.00                                                G)    Carbomer 934 (e.g. Carbopol 934 P)                                                                1.00                                                E)    Sorbitan monolaurate (e.g. Span 20)                                                               1.00                                                F)    Polysorbate 20 (e.g. Tween 20)                                                                    5.00                                                H)    Ethanol 94 % w/w    10.00                                               B)    Isopropyl myristate 10.00                                                     Water demineralized 70.88                                               ______________________________________                                    

A pharmaceutically acceptable emulsion gel is obtained from the aboveingredients, when the preparation process is carried out in thefollowing steps:

A, B, C, D, E and F are mixed together with slight warming until allsolid particles are dissolved;

II. in an appropriate vessel or processor containing a stirrer and ahomogenizer about half of the water is heated to 60°-70°;

III. I is slowly added to II while stirring and homogenizing until ahomogenous emulsion with appropriate droplet size is obtained. Theconcentrated emulsion is then cooled to r.t.;

IV. in a separate vessel a basic carbomer gel is prepared by dispersingcarbomer in H and the second half of the water and neutralizing with I;

V. the basic emulsion III is added to the basic gel and the whole isstirred at r.t. until a homogeneous emulsion gel is obtained.

EXAMPLE 5 Emulsion Gel 1%

    ______________________________________                                        Ingredient            Amount (g/100 g)                                        ______________________________________                                        A)    Compound I in free base form                                                                      1.00                                                C)    Butyl hydroxy toluene                                                                             0.02                                                I)    Sodium hydroxide pellets                                                                          0.10                                                D)    Benzyl alcohol      0.50                                                G)    Carbomer 934 (e.g. Carbopol 934 P)                                                                1.00                                                E)    Sorbitan monolaurate (e.g. Span 20)                                                               1.00                                                F)    Polysorbate 20 (e.g. Tween 20)                                                                    5.00                                                H)    Ethanol 94 % w/w    10.00                                               B)    Isopropyl myristate 10.00                                                     Water demineralized 71.33                                               ______________________________________                                    

A pharmaceutically acceptable emulsion gel is obtained from the aboveingredients, when the preparation process is carried out in thefollowing steps:

I. A, B, C, D, E and F are mixed together with slight warming until allsolid particles are dissolved;

II. in an appropriate vessel or processor containing a stirrer and ahomogenizer about half of the water is heated to 60°-70°;

III. I is slowly added to II while stirring and homogenizing until ahomogenous emulsion with appropriate droplet size is obtained. Theconcentrated emulsion is then cooled to r.t.;

IV. in a separate vessel a basic carbomer gel is prepared by dispersingcarbomer in H and the second half of the water and neutralizing with I;

V. the basic emulsion III is added to the basic gel and the whole isstirred at r.t. until a homogeneous emulsion gel is obtained.

EXAMPLE 6 Lotion 1%

    ______________________________________                                        Ingredient           Amount (g/100 g)                                         ______________________________________                                        A)     Compound I in free base form                                                                    1.00                                                 C)     Propyl p-hydroxybenzoate                                                                        0.03                                                 D)     Methyl p-hydroxybenzoate                                                                        0.10                                                 G)     Ammonia solution 25 % w/w                                                                       0.36                                                 F)     Carbomer (e.g. Carbopol 1342)                                                                   0.60                                                 B)     Isopropyl myristate                                                                             5.00                                                 H)     Ethanol 94 % w/w  10.00                                                E)     Water demineralized                                                                             82.91                                                ______________________________________                                    

A pharmaceutically acceptable lotion is obtained from the aboveingredients, when the preparation process is carried out in thefollowing steps:

I. A is dissolved in B at r.t.;

II. in an appropriate processor containing a stirrer and an efficienthomogenizer C and D are dissolved in E while heating up to 90°. Thesolution is then cooled to about 30° to 40°;

III. F is dispersed in II. The homogenous dispersion is then neutralizedwith G, resulting in an opalescent thickened solution;

IV. the organic solution I is then emulsified into the thickenedsolution III by stirring and homogenizing until a lotion withappropriate droplet size (2 to 20 μm) is obtained;

V. finally H is added to IV and the whole is stirred until the finalproduct is obtained.

We claim:
 1. A topical pharmaceutical composition comprising as theactive agent a terbinafine compound of formula I ##STR3## in free baseform or in acid addition salt form, water, a lower alkanol, and awater-soluble or water-miscible nonionic surfactant, wherein no anionicsurfactant is present.
 2. A composition according to claim 1 containingfrom 50 to 85% by weight of water.
 3. A composition according to claim 1containing 5 to 35% by weight of a lower alkanol.
 4. A compositionaccording to claim 3 wherein the alkanol is ethanol.
 5. A compositionaccording to claim 1 which is substantially free of fatty material.
 6. Acomposition according to claim 1 wherein said composition is a spray, agel or a fluid gel.
 7. A composition according to claim 1 wherein saidsurfactant is a polyoxyethylene fatty alcohol ether.
 8. A compositionaccording to claim 1 wherein the weight ratio of said active agent tosaid surfactant is from about 1:0.5 to about 1:15.
 9. A compositionaccording to claim 1 wherein the compound of formula I is present fromabout 0.1% to about 5% of the total weight of the composition on a w/wbasis.
 10. A method for the treatment of seborrhoic skin comprisingadministering a pharmaceutically effective amount of a compositionaccording to claim 1 to a patient in need of such treatment.
 11. Acomposition according to claim 7, wherein the weight ratio of saidactive agent to said surfactant is from about 1:0.5 to about 1:15.
 12. Atopical pharmaceutical composition in the form of an emulsion, saidemulsion comprising an oil phase containing a terbinafine compound ofthe formula I ##STR4## in free base form or in acid addition salt form,and an aqueous phase comprising water, a lower alkanol, and awater-soluble or water-miscible nonionic surfactant, wherein no anionicsurfactant is present.
 13. A composition according to claim 12containing isopropyl myristate as the oil phase.
 14. A compositionaccording to claim 12, wherein the weight ratio of said active agent tosaid oil phase is from about 1:5 to about 1:40.
 15. A compositionaccording to claim 13, wherein the ratio between the compound of formulaI and the oil phase is from about 1:5 to about 1:40 on a w/w basis.